2025 Nobel Prize in Physiology or Medicine: Brunkow, Ramsdell & Sakaguchi Reveal Peripheral Immune Tolerance Mechanism
On October 6, 2025, the Nobel Assembly at the Karolinska Institute announced that the 2025 Nobel Prize in Physiology or Medicine would be awarded to Mary E. Brunkow, Fred Ramsdell, and Shimon Sakaguchi for their landmark discoveries regarding peripheral immune tolerance.
This award recognizes their insights into how the immune system is regulated beyond the central (thymic) checkpoints, ensuring that self-reactive immune cells do not cause damage to healthy tissues. Their findings open up promising avenues for treating autoimmune disorders, transplant rejection, and immune modulation in cancer.
Laureate Profiles
Mary E. Brunkow
Mary Brunkow is a senior program manager at the Institute for Systems Biology in Seattle. AP News+2Reuters+2 Her scientific focus has been on immunology, especially connecting genetic insights to immune regulation. She played a key role in linking mutations in the FOXP3 gene to pathological immune self-reactivity in mouse models and human disease.
Fred Ramsdell
Fred Ramsdell is a scientific adviser at Sonoma Biotherapeutics in San Francisco. AP News+1 He collaborated with Brunkow in investigating the functional consequences of FOXP3 mutations and how these impact the development and function of regulatory T cells (Tregs).
Shimon Sakaguchi
Shimon Sakaguchi is a distinguished professor at the Immunology Frontier Research Center at Osaka University, Japan. He was pivotal in first identifying regulatory T cells in 1995 and elucidating their role in suppressing immune responses, setting the foundation for the later genetic discoveries.
While their geographical and institutional bases differ, the synergy of their contributions has reshaped immunology.
The Science: Peripheral Immune Tolerance
Central vs Peripheral Tolerance
The immune system has built-in checks to prevent self-damage. Central tolerance occurs mainly in the thymus, where T cells that react too strongly to self-antigens are eliminated during development. Yet, this is not foolproof—some self-reactive T cells can escape. Thus, an additional level of control is needed in the peripheral tissues (blood, lymph nodes, organs).
This is where peripheral immune tolerance comes in: mechanisms that suppress, regulate, or eliminate rogue immune cells that eluded thymic deletion.
Regulatory T Cells (Tregs) and FOXP3
Sakaguchi’s work in 1995 introduced the idea of regulatory T cells—a population of T cells that actively suppress immune responses. These cells help maintain tolerance by inhibiting overly aggressive immune reactions.
Later, Brunkow and Ramsdell helped identify the FOXP3 gene as a central regulator of Treg cell function. They found that mutations in FOXP3 disrupt Treg development or function, leading to severe autoimmunity in both mice and humans (e.g. the IPEX syndrome).
By linking a genetic mutation to immune dysregulation, they showed how a breakdown in peripheral control can result in disease. Together, their work clarified how Tregs operate, how FOXP3 controls their identity and function, and how peripheral tolerance is enforced.
Experimental Foundations
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Knockout mouse models lacking functional FOXP3 show lethal autoimmune disease, underscoring the gene’s central role.
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Human patients with FOXP3 mutations manifest systemic autoimmunity, confirming the clinical relevance.
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Functional assays confirmed that FOXP3-expressing Tregs suppress other immune cells.
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Molecular studies mapped how FOXP3 interacts with other transcription factors and chromatin to maintain Treg identity.
These experiments bridged molecular genetics, cellular immunology, and clinical pathology to paint a coherent picture of immune regulation.
Therapeutic & Clinical Implications
Autoimmune Diseases
Many autoimmune conditions (type 1 diabetes, lupus, multiple sclerosis, rheumatoid arthritis) result from failures in immune tolerance. Understanding Treg biology and FOXP3 gives new levers to restore balance. Therapies might aim to enhance Treg function or stability, or correct genetic defects.
Transplantation
One of the biggest challenges in organ transplantation is preventing the immune system from rejecting the new organ. Harnessing or engineering Tregs could enable more selective immunosuppression, avoiding global immune suppression.
Cancer & Immunotherapy
Paradoxically, in cancer, one might suppress Treg activity to unleash anti-tumor immunity. Thus, understanding how Tregs are regulated informs strategies to fine-tune immune responses: boosting them in autoimmunity or dialing them down in cancer.
Challenges Ahead
Translating from bench to bedside is nontrivial:
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Ensuring Treg stability in diverse inflammatory environments.
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Avoiding unintended immunosuppression (higher infection risk).
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Tailoring approaches to individual patient genetics and disease contexts.
Reactions & Significance
The Nobel Committee praised the trio for revealing “how we keep our immune system under control so we can fight pathogens yet avoid autoimmune disease.”
Their award is widely seen as a milestone in immunology. Scholars note that bridging genetics, cell biology, and immunoregulation exemplifies the interdisciplinary character of modern biomedical breakthroughs.
It also continues a lineage of Nobel awards recognizing immune regulation (e.g. T cell biology, cytokines).
Place in Nobel History
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This marks a Nobel in Medicine focused on immune regulation and tolerance.
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Among previous laureates, only a few have been recognized for autoimmune or immune system control.
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Brunkow is one of the relatively smaller number of women Nobel laureates in medicine.
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It underscores the global nature of scientific discovery: cross-country collaboration, building on decades of prior work.
Future Directions
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Clinical trials of Treg-based therapies (cell therapy, gene editing).
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Better biomarkers to monitor Treg stability and function in patients.
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Deeper molecular maps of FOXP3’s interactions and downstream targets.
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Exploring heterogeneity among Treg subsets in tissues.
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Integrating insights into personalized immunomodulatory treatment.
Conclusion
The 2025 Nobel Prize in Medicine awarded to Mary Brunkow, Fred Ramsdell, and Shimon Sakaguchi recognizes a transformative understanding of how our immune system is kept in check—not only in development but in the periphery. Their work reveals the delicate balance between protection and self-harm, unlocking new possibilities for addressing autoimmune disorders, transplant medicine, and immunotherapy.
The Nobel Prizes were created for a single, overarching purpose: to honor those who, during the preceding year, shall have conferred the greatest benefit to humankind.
The prizes are the lasting legacy of their founder, Alfred Nobel (1833–1896), a Swedish chemist, engineer, and industrialist famous for inventing dynamite.
As the rest of the 2025 Nobel laureates are announced, we’ll gain a fuller picture of this year’s scientific and humanistic advances. Let me know when you’d like me to draft the full articles for the other categories.
